MXPA96004755A - Process and apparatus for molar continuing pharmaceutical results in aerosol and propellers in aero - Google Patents

Abstract

The present invention relates to a process for the preparation of an aerosol pharmaceutical formulation containing a solid therapeutic agent, which comprises the steps of: a) mixing the solid therapeutic agent with a liquid propellant having a lower boiling point 25C, to form a mixture comprising up to 99% by weight of said liquid propellant, b) repeatedly passing the mixture formed in step (a) between a first refrigerated supply tank and a second refrigerated receiving tank through of a grinding apparatus until the particle size of the solids contained in the mixture is reduced to less than 10æ, keeping the first refrigerated supply tank and the second cooled receiving tank at a temperature between -80§C and 10§ C approximately, and c) subsequently loading the mixture of the solid therapeutic agent and the propellant into aerosol cans

Description

~ r- PROCESS AND APPARATUS FOR CONTINUOUSLY MOLARING PHARMACEUTICAL FORMULATIONS IN AEROSOL AND PROPELLERS IN AEROSOL Field of the Invention The present invention relates to manufacturing processes and apparatus for preparing pharmaceutical formulations. More particularly, the present invention relates to an apparatus and process for the preparation of pharmaceutical aerosol formulations by f grinding the formulation in the aerosol propellant.

Background of the Invention It is desirable to apply certain therapeutic agents to patients in the form of an aerosol spray. This mode of administration is particularly suitable for situations where the desired medication site is the upper respiratory tract, and also in those situations where systemic administration is desired, but the therapeutic agent can not be applied orally. Peptide therapeutics, for example, are generally degraded by enzymes present in the mouth and in the alimentary tract, and must be applied either via a parenteral route or directly to the lungs of the patient by means of an aerosol spray. The last route of administration is preferred by patients as more convenient and less invasive. Aerosol pharmaceutical formulations can take the form of either a liquid or solid therapeutic agent suspended or dissolved in a suitable vehicle and a propellant. The preparation of aerosols in which the active component is a liquid is rather direct. However, in the case of solid therapeutic agents, the preparation of aerosol dosage forms is a little more complicated. Typical processes for the preparation of aerosol formulations containing solid therapeutic agents involve a multi-step process wherein the solid components of the aerosol dosage form are first milled in air or in a liquid milling medium to obtain the size of desired particles. In a second step, where the solids were milled in a liquid medium, the grinding medium is removed by filtration or evaporation to leave a cake of the solids. In any case, the cake of solids resulting from the grinding step is then decomposed and passed through sieves of the appropriate size to remove any aggregates that may be present. The resulting powder, of the desirable particle size scale, is then mixed with the aerosol propellant, and with any desired liquid vehicles or additives, and filled into aerosol cans intended for use by the patient.

The process of grinding in air suffers from the drawbacks of a possible contamination of solids by moisture (with the formation of cake and accumulation together) and the need for containment facilities to prevent dust explosion and worker exposure. The liquid milling process suffers from similar drawbacks. The use of a liquid milling medium, although it helps in the efficient reduction of the particle size of the solids, requires additional steps of their removal and subsequent treatment of the resulting solids cake. Moreover, the step of sifting the milled solids often requires special equipment or containment precautions to prevent in the same way the contamination of the dry solid by moisture, dust explosion hazards, or exposure of the worker to the therapeutic agent. Although in most cases the solid aggregates that are screened in the sieve step can be recycled in the process, there are some resulting losses that can introduce unacceptable processing costs in those cases where the therapeutic agent is expensive. In addition, the liquid grinding medium, which can not be completely removed from the final product during the processing of the aerosol formulation, is itself a source of contamination of the final product. Finally, both grinding in air and liquid causes the generation of heat, which can cause the degradation of the therapeutic agent in certain cases.

BRIEF DESCRIPTION OF THE DRAWING In the drawing, Figure 1 is a schematic representation of the process and apparatus of the present invention.

SUMMARY OF THE INVENTION The present invention overcomes these drawbacks by providing an apparatus and process for the preparation of pharmaceutical aerosol formulations containing solid components. In its embodiment of the process, the invention comprises the step of grinding the solid components of the formulation directly into the material that serves as the propellant in the final aerosol formulation. The process retains in this way the advantages of grinding in a liquid medium, but eliminates the need to use u? different liquid milling medium, which must be removed before mixing the solid components of the aerosol formulation with the propellant. In its embodiment of the apparatus, the present invention comprises an apparatus for continuously grinding aerosol pharmaceutical formulations in an aerosol propellant, which comprises: a) a first supply tank having a cooling element for containing a supply of pharmaceutical formulation in aerosol; b) a second receiving tank having a cooling element; c) a grinding apparatus interconnected between the supply and receiving tanks, to reduce the size of solid particles of the aerosol pharmaceutical formulation; d) a pump element for passing the aerosol pharmaceutical formulation from the first supply tank through the grinding machine and up to the second receiving tank; and e) a cooling element for circulating a refrigerant through the cooling element of the first supply tank and the second receiving tank.

Detailed Description Throughout this specification and the appended claims, the term "propellant / milling media" is used to denote the material that is employed in the milling process for liquid milling of the solid therapeutic agent, and any solid ingredients additional of the aerosol formulations, and that remains in the aerosol formulation to finally work on the propellant role. The propellant / milling medium is selected from materials wherein the desired therapeutic agent is insoluble, in order to produce a final aerosol formulation wherein the therapeutic agent is suspended in a finely divided particle form. In certain situations, two or more therapeutic agents may be incorporated into the final aerosol formulation. In these cases, the different therapeutic agents can be ground together in the propellant / milling medium, or, alternatively, the therapeutic agents can be ground separately in the same propellant / milling medium or in a different one, up to the size or sizes of desired particles, and the resulting suspensions are mixed before filling the aerosol cans. The latter alternative is useful in those cases where the nature of the two or more therapeutic agents is such that the scales of desired particle sizes for the agents are different. In the same way, it is possible to use two or more mixed materials such as the propellant / milling medium. Alternatively, the therapeutic agent or mixture of agents can be milled in a single propellant / milling medium, and one or more propellant materials are added in later stages of the process. It should be noted, however, that in all variants of the process described above, the process of the present invention does not involve removing the aggregate material during the process steps. That is, each ingredient added to the aerosol formulations during processing becomes part of the final formulation and is present in the final formulation. In this way, the process of the present invention differs from prior art processes for the preparation of solid aerosol formulations, where the aggregate grinding media during the grinding steps must be removed before the final formulation of the aerosol. Suitable materials to be used as the propellant / milling medium in the process of the present invention are those materials which have a high vapor pressure at room temperature, which are chemically compatible with the therapeutic agent or agents contained in the formulation in aerosol, and wherein the agent or therapeutic agents are not soluble. Representative propellant / milling media for use in the process of the present invention includes, lower boiling alkanes, low boiling halogenated lower alkanes, lower low boiling cycloalkanes, low halogenated lower cycloalkanes boiling, low boiling di (lower alkyl) ethers, low boiling point di (lower alkyl) ethers, low boiling di (lower alkyl) thioethers, and low point halogenated di (lower alkyl) thioethers of boiling, and the like. These materials include, by way of example, chlorodifluoromethane, chlorotrifluoromethane, dichlorodifluoromethane, trichlorofluoromethane, tetrachloroethane, 1,2-dichlorotetraf luoroethane, t riclorof luoroethane, chloropentafluoropropane, chlorheptafluoropropane, heptafluoropropane, perfluorocyclopropane, perfluoropropane, per luorobutane normal, per f luoroi sobu t anus, perfluorocyclobutane, perfluorodimethyl ether, perfluorodimethyl ether, perfluorofuran, perfluoromethyl amine, bis- (trifluoromethyl sulfone), bis- (trifluoromethyl sulfide), and trifluoromethyl pentafluorosulfide, and the like. The term "lower alkane" and "cycloalkane" Lower V "means straight or branched or cyclic saturated hydrocarbons of 1 to 10 carbon atoms.The term" low boiling point "means boiling points below the temperature of the human body.The preferred propellant / grinding medium is from those materials which have boiling points below about 25 ° C. Although chlorofluorocarbon materials can be conveniently used in the process of this invention, the current trend in the industry moves away from the use of these chlorine-containing materials, due to the effects Adverse to the environment The preferred propellant / grinding media in the process of the present invention, therefore, includes partially or fully fluorinated hydrocarbons (ie, "perfluoro"). Particularly preferred propellants / grinding media are tetrafluoroethane and heptafluoropropane The process of the present invention can be used to prepare formula Solid aerosol ions for any solid therapeutic agent for which aerosol administration is a desirable route of administration. Examples include peptides, protein materials, and other agents that do not lend themselves to oral administration, such as interferons and other macrophage activation factors; erythropoietin and other glycoproteins; opioid peptides, neuropeptides, encephalinas, endorphins, dynorphins, peptide renin inhibitors and pseudopeptides; cholecystokinins, such as cerulitide, and eledoisin; leukotrienes and prostaglandins; peptidomimetics; insulin, oxytocin antiasthmatic agents, and pharmaceutically acceptable salts, esters, and prodrugs of any of the foregoing. Specific examples of therapeutic agents that fall within the aforementioned general classes include, but are not limited to, LHRH agonists and antagonists, such as leuprolide and its salts (particularly acetate), antiallergic and antiasthmatic agents such as urea N -hydroxy-N- (1-benzo [b] thien-2-yl) ethyl) (also known by its generic name "zileuton"), anti-inflammatory agents such as beclomethasone; Albuterol; isoproterenol; ipratropium flunisolide; terbutaline; pirbuterol; triamcinolone; and the pharmaceutically acceptable salts, esters, or prodrugs of any of the foregoing. In the aerosol formulations made by the process of the present invention, the propellant / milling media can comprise up to 99.9 percent of the mixture. Additional components of the aerosol formulations made by the process of the present invention include surfactants that are compatible with the agent or It therapeutic agents incorporated in the formulations, and where the agent or therapeutic agents are not soluble. Suitable surfactants include, but are not limited to, sorbitan monooleate, sorbitan triolate, sorbitan monolaurate, polyoxyethylene sorbitan monooleate (20), polyoxyethylene sorbitan monolaurate (20), sodium lauryl sulfate, cholesterol, natural and synthetic lecithins, oleyl polyoxyethylene, stearyl polyoxyethylene, lauryl polyoxyethylene, oxyethylene and oxypropylene block copolymers, oleic acid, glycol dioleate of diethylene, tetrahydrofuryl oleate, ethyl oleate, isopropyl myristate, glyceryl trioleate, glyceryl monolaurate, glyceryl monostearate, cetyl alcohol, polyethylene glycol 440, cetyl pyridinium chloride, and natural oils such as those derived from from corn, olive trees, cottonseed, and sunflower seed. In the formulations, the surfactant component generally comprises up to about 3 percent of the formulation. Because the propellant / grinding media has a boiling point near or below the ambient temperature, it must be kept refrigerated during the grinding process, typically at temperatures between about -80 ° C and about 10 ° C. This cooling also has the advantage of cooling the mixture that is being milled, which prevents any thermal degradation of the sensitive therapeutic agents This is done in the preferred embodiment of the process of the present invention by consecutive steps of the mixing of propellant / grinding medium through the grinding machine between two tanks that alternate, respectively, as the tanks of supply and receiving, both of which are double-walled with provision for circulating a coolant through a cooling jacket between the walls of the tank, or through cooling coils disposed inside the tanks. The mixture is passed back and forth through the mill until the desired particle size is obtained for the solids content of the mixture. The particle size can be monitored by periodically removing an aliquot sample from the system for the analysis of the size of the particles by conventional methods, or more - conveniently, by continuous particle size analysis in the stream by optical elements, such as a laser light scattering particle size analyzer incorporated in the process stream. The analysis of the particle size in the stream can be conveniently carried out by using, for example, a particle size laser reverse diffuse particle size analyzer model Partee * 100 available from Lasentec, Duluth, GA. The grinding is carried out by using, for example, a ball mill of the type conventionally used in the pharmaceutical formulating art, such as a "Dyno-Mill Type KDL" or "Dyno-Mill Type KDL Special" unit manufactured by .A. Bachofen AG, Basel, Switzerland. The grinding machine can be adapted with a cooling jacket that surrounds the mechanical seal of the rotating shaft of the mill, to counteract the production of heat generated during the milling operation. In a particularly unique feature of the process of the present invention, the refrigerant is circulated through both the cooling jacket of the tank and the mechanical seal jacket of the grinding machine, and is selected to be identically the same material as that employed as the propellant / grinding medium in the grinding process. This ensures that any leakage of refrigerant to the milled formulation that may occur in the mechanical seal of the mill, does not result in contamination of the batch being milled. In Figure 1 a schematic representation of the apparatus used in the preferred embodiment of the process appears. In Figure 1, the process power lines and the refrigerant supply lines are shown as double lines, while the electric or electronic signal lines are shown as fine lines with an arrowhead at one end indicating the direction of the signal flow. In the preferred embodiment, the process of the invention is carried out using an apparatus that is constructed in modules, which are interconnected by means of quick connection and quick disconnect accessories of the type well known in the pharmaceutically processing art. Tanks 10 and 20 are mounted on wheels to allow their movement to their position for the milling process, and to subsequently move to a location where they serve as supply vessels for the subsequent operation of filling the aerosol can. The tanks are double walled to allow the circulation of a coolant or cooler through a cooling jacket between the inner and outer walls to cool the contents of the tank as necessary, and are also constructed to contain pressures above atmospheric. In an alternative mode, the double-walled construction of the tank serves for an insulating function, and the contents of the tank are cooled by circulating refrigerant through the coils located inside the tanks. The ball mill 40, the mechanical seal jacketed 50, and the associated pipe, valves, and electronic sensor arrangement, are conveniently mounted on a single bearing, so that they can be moved into place during the milling process, or can be removed for cleaning. or for any necessary repair An electronically programmable control apparatus 60 receives and processes the electrical signals from different sensors located throughout the system, to control the flow of refrigerant, to open and close the valves as required, and to process other signals such as those from the particle size analyzer in the stream. A heat exchanger 30 receives the cooling water or other commercial refrigerant such as Freon * through valve 350 and line 180, to cool the refrigerant or cooler, which is circulated through the refrigerant feed line 200. to the cooling jacket of the tank 10, through the refrigerant supply line 210 to the cooling jacket of the tank 20, and through the refrigerant supply line 220 to the cooling jacket of the mechanical seal 50 of the ball mill 40. In a control feedback cycle, temperature sensors submerged in the contents of tank 10 send an electrical signal through signal line 400 to controller 70, which, in turn, sends a control signal to the electrically operated valve 520, which controls the flow of refrigerant through the refrigerant supply line 200, to control the temper atura of the content * of the tank. In a similar manner, the temperature sensors in tank 20 operate in conjunction with controller 70 through signal lines 410 and 420, and electrically operated valve 510, to supply refrigerant through line 210, to control the temperature of the 5 contents of the tank. The mechanical heat generated in the mechanical seal 50 of the ball mill 40 during the milling process, and which would otherwise cause an unacceptable rise in the vapor pressure of the propellant / milling media, is controlled or similarly by the circulation of refrigerant through the refrigerant supply line 220 to a cooling jacket surrounding the mechanical seal 50. A temperature sensor in the mechanical seal 50 communicates with the controller 70 through the signal line 440, and the The controller, in turn, signals the electrically controlled valve 500 through the signal line 450, to control the flow of refrigerant to the mechanical seal 50. A unique feature of the process of the present invention is that the refrigerant used in the cooling of the contents of tanks 10 and 20 and mechanical seal 50 is the same as the liquid used as the propellant / m grinding edio. In this way, any introduction of refrigerant from the cooling jacket of the mechanical seal 50 to the contents of the lt. Ball mill 40 during grinding, as a result of pressure differences, does not result in contamination of the material in the system. In the grinding of a typical batch of aerosol formulation that employs the process and apparatus of the present In the invention, the propellant / milling medium is charged through the feed line 100 and the valve 300 to the tank 10. The solid to be ground is then mixed, together with other components of the formulation, such as surfactants, with the propellant / grinding medium, under gas nitrogen or other suitable dry inert gas. The mixing of the materials in any tank 10 or 20 is carried out more conveniently by means of magnetic stirrers located in the tanks. This eliminates the problems of contamination or pressure leaks, which could otherwise occur with the use of mechanical agitators whose arrows must pass through the wall of the tanks. The mixture of solids and propellant / milling medium contained in the tank 10, is then transferred through the valve 310 and the supply line 110 and the three-way valve 320, to the pump 80, which forces the mixing through the feed line 130 and up to the ball mill 40. The material leaves the ball mill 40 through the feed line 150, where it passes through an on-line particle size analyzer 60. From there, the material passes through the three way valve 340 and the feed line 170 to the tank 20, which serves as the receiving tank for the first pass of the material through the grinding process. When tank 10 of its formulation charge has been emptied, the process is reversed. That is, the tank 20 now serves as the supply tank, and the tank 10 serves as the receiving tank for a second pass of the material through the grinding machine. In this case, the material leaves the tank 20 through the valve 330 and the feed line 140, to pass through the three-way valve 320 and the pump 80, which forces the mixture through the mill. balls 40. The material exiting the ball mill 40 passes through the on-line particle size analyzer 60, and the three-way valve 340, but is now directed through line 160 to the tank 10, the which serves as the reception tank. This process is repeated with multiple passes through the ball mill 40, until the desired reduction in solid particle size has been achieved. This event is signaled by the on-line particle size analyzer 60, which sends a signal through the signal line 430 to the controller 70, which then signals the deactivation of the grinding process. The tank that contains the formulation at the end when the desired particle size has been reached, is then disconnected from the system, and carried on wheels to the place where it serves as the supply tank for the next operation of filling the can of aerosol. The following examples are typical of aerosol formulations that can be prepared by the process of the present invention, and are provided to enable an expert in the field to practice the invention. The examples are to be seen as merely illustrative of the invention, and should not be read to limit their scope as defined in the appended claims. In each of the examples, the therapeutic agent, the surfactant, and the propellant / milling medium, are mixed in the initial supply tank of the process apparatus under dry nitrogen gas. The mixture is passed through the mill to the receiving tank, and back again to the initial tank, until the desired particle size is reached, generally less than about 10 microns. At this point, the tank containing the milled formulation is disconnected from the system, and moved to the place where the formulation is filled into aerosol cans, and the cap and valve assembly is connected by conventional elements known in the art.

Example 1 A solid aerosol pharmaceutical formulation containing leuprolide acetate is prepared, by mixing 24 to 28 parts by weight of trichlorofluoromethane, 72 to 76 parts by weight of dichlorofluoromethane, 0.3 to 0.6 parts by weight of sorbitan trioleate, and 10 milligrams / milliliter of leuprolide acetate, the resulting mixture is ground to a particle size less than about 10 microns, the resulting milled mixture is loaded into pressurized aerosol cans, and the cap and valve stem assembly is connected and sealed to the filled cans.

Example 2 A solid aerosol pharmaceutical formulation containing leuprolide acetate is prepared by mixing 24 to 28 parts by weight of trichlorofluoromethane, 72 to 76 parts by weight of dichlorodifluoromethane, 0.3 to 0.6 parts by weight of sorbitan trioleate, and 20 milligrams / milliliter of leuprolide acetate, the resulting mixture is milled to a particle size of less than about 10 microns, the resulting milled mixture is loaded into pressurized aerosol cans, and the cap and rod assembly is connected and sealed. 5 valve to filled cans.

Example 3 A solid aerosol pharmaceutical formulation containing leuprolide acetate is prepared by mixing IX. of 25 parts by weight of trichlorofluoromethane, 74 parts by weight of dichlorodifluoromethane, 0.3 parts by weight of sorbitan trioleate, and 10 milligrams / milliliter of leuprolide acetate, the resulting mixture is milled to a particle size of less than about 10 microns , the The resulting milled mixture is filled into pressurized aerosol cans, and the cap and valve stem assembly is connected and sealed to the filled cans.

Example 4 A solid aerosol pharmaceutical formulation containing leuprolide acetate is prepared by the mixture of 25 parts by weight of trichlorofluoromethane, 99 parts by weight of tetrafluoroethane, 0.1 parts by weight of sodium lauryl sulfate, 0.1 parts by weight of cholesterol , and 10 milligrams / milliliter of zileuton, the resulting mixture is milled to a particle size of less than about 10 microns, the resulting milled mixture is loaded into pressurized aerosol cans, and dried. connects and seals the cap and valve stem assembly to the filled cans.

Claims (11)

1. In a process for the preparation of aerosol pharmaceutical formulations containing 5 solid components, which comprises the steps of: (a) grinding the solid components of the formulation in a liquid grinding medium, (b) removing the liquid grinding medium, (c) breaking the cake of solids resulting from step (b), (c) sifting the broken cake from step (c) to obtain solids that have the desired scale of particle sizes, (d) mixing the sifted solids with the aerosol propellant, and (e) loading the mixture resulting from step (d) into aerosol cans, the improvement comprising grinding the solids in a material that finally works with the propellant in the 15 aerosol formulation, thereby eliminating steps (a) to (c).

2. The process according to claim 1, wherein the material used as well as the milling medium and the propellant, is selected from the group that 20 consists of low-boiling lower alkanes, lower-boiling halogenated lower alkanes, lower-boiling low-cycloalkanes, low-boiling halogenated lower cycloalkanes, low-boiling di (lower alkyl) ethers, lower boiling diethylene (lower alkyl) ethers, low boiling di (lower alkyl) thioethers, and low boiling point di (lower alkyl) thioethers.

3. The process according to claim 1, wherein the material employed as both the grinding medium and the propellant, is selected from the group consisting of: chlorodifluoromethane, chlorotrifluoromethane, dichlorodifluoromethane, trichlorofluoromethane, tetrachloroethane, l * ' 1, 2-dichlorotetrafluoroethane, trichlorofluoroethane, c1 oropenfluoropropane, chlorheptafluoropropane, heptafluoropropane, perfluorocyclopropane, perfluoropropane, pe rf luor ob u t a tio nal, per f luoroi s ob tu re, perfluorocyclobutane, perfluorodimethyl ether, perfluorodimethyl ether, perfluorofuran, amine perfluoromethyl, bis- (trifluoromethyl sulfone), bis- (trifluoromethyl sulfide), and trifluoromethyl pentafluorosulfide.

4. The process according to claim 1, wherein the material used as well as the grinding medium and the propellant is tetrafluoroethane.

5. The process according to claim 1, wherein the material employed as both the grinding medium and the propellant is heptafluoropropane.

6. The process of claim 1, wherein the mixture of propellant material and therapeutic agent is repeatedly passed from a first refrigerated supply tank to a second refrigerated receiving tank, through a grinding machine, until the size of particles of the solids contained in the mixture is reduced to a predetermined maximum. The process of claim 6, wherein the previously determined maximum particle size is determined by continuous monitoring of the process stream. 8. An apparatus for continuously grinding aerosol pharmaceutical formulations, in an aerosol propellant, which comprises: a) a first supply tank having a cooling element for containing a supply of aerosol pharmaceutical formulation; b) a second receiving tank having a cooling element; c) a ball mill apparatus interconnected between the supply and repeat tanks, to reduce the size of solid particles of the aerosol pharmaceutical formulation; d) a pump element for passing the aerosol pharmaceutical formulation from the first supply tank through the grinding machine and up to the second receiving tank; and e) a cooling element for recirculating a refrigerant through the cooling element of the first supply tank and the second receiving tank. 9. An apparatus according to claim 8, which further comprises an element for continuously monitoring in the stream the size of solid particles of the aerosol pharmaceutical formulation, as it passes from the first supply tank to the second receiving tank. 10. An apparatus according to claim 8, which further comprises an element for cooling the ball milling apparatus. 11. An apparatus according to claim 8, wherein the refrigerant and the propellant component of the aerosol pharmaceutical formulation are the same material.